Pharmaceutical composition containing acetominophen and ibuprofen

ABSTRACT

Solid oral dosage forms containing 325 mg of acetaminophen and 97.5 mg of ibuprofen or 500 mg of acetaminophen and 150 mg of ibuprofen, wherein the ibuprofen has a [D50] between 1 and 9 μm, are described.

RELATED APPLICATIONS

This application is a continuation and claims priority to U.S.application Ser. No. 17/548,877, filed on Dec. 13, 2021, which is acontinuation and claims priority to U.S. application Ser. No.16/287,836, filed on Feb. 27, 2019, (U.S. Pat. No. 11,197,830) theentire contents of which are hereby incorporated by reference.

BACKGROUND

For various non-steroidal anti-inflammatory drugs (NSAIDs) there isevidence that high, early plasma concentrations result in better earlypain relief, better overall pain relief, longer lasting pain relief andlower rates of remedication. (Moore et al. (2015) British Journal ofClinical Pharmacology 80:381). For ibuprofen, more rapid absorption canresult in earlier and higher maximum plasma concentrations and thisresults in earlier onset of analgesia and better overall and longerlasting analgesia in dental pain models. The effect of fast actingformulations can be significant. In one study 200 mg of a fast actingformulation, a ibuprofen salt produced the same or better analgesia as400 mg ibuprofen acid, and with a reduced requirement for additionalanalgesic use (Moore et al. (2014) Pain 155:14). It is possible to alterthe pharmacokinetics of ibuprofen by reducing the particle size to below1000 nm (WO 2010/121328)

SUMMARY

Described herein is a solid oral unit dosage pharmaceutical compositioncontaining acetaminophen (325 mg) and ibuprofen (97.5 mg) having ahigher maximum plasma concentration for ibuprofen compared to Maxigesic(325). Also described is a solid oral unit dosage pharmaceuticalcomposition containing acetaminophen (500 mg) and ibuprofen (150 mg).These dosage forms are referred to as Rapid Maxigesic 325 and RapidMaxigesic 500, respectively. This disclosure features thesepharmaceutical compositions as well as methods for producing and usingsuch compositions.

The solid oral dosage forms described herein include ibuprofen (freeacid) that is particularly rapidly dissolving in vitro. The impact ofincreased in vitro dissolution rates on pharmacokinetic parameters ishighly variable. In the case of the present dosage forms, the rapidlydissolving ibuprofen results in a product with meaningfully higher Cmaxfor ibuprofen. Significantly, the ibuprofen in the present dosage formshas a particle size that is larger than 1,000 nm.

Described herein is a solid oral dosage form comprising 325 mg ofacetaminophen and 97.5 mg of ibuprofen or 500 mg of acetaminophen and150 mg of ibuprofen, wherein the ibuprofen has a [D50] between 1 and 9μm.

In various embodiments: the ibuprofen has a [D10] between 1 and 3 μm;the ibuprofen has a [D90] between 3 and 16 μm; the ibuprofen has a [D50]between 2 and 8 μm, a [D10] between 1 and 3 μm and a [D90] between 4 and16 μm; the dissolution rate of ibuprofen in the solid oral dosage formis such that, when tested using USP Apparatus II (paddles) set torotation speed of 50 rpm in 900 mL of 50 mM pH 5.8 phosphate buffer at37° C., wherein 80% or more (e.g., at least 85% to 95% or 95% to 100%)of the ibuprofen dissolves in 15 minutes or less; the dosage form is atablet (e.g., a coated tablet); the [D90] to [D50] ratio is between 4:1and 1.5:1; the [D90] to [D50] ratio is between 3:1 and 1.5:1; the [D50]to [D10] ratio is between 4:1 and 1.5:1; and the [D50] to [D10] ratio isbetween 3:1 and 1.5:1.

In some cases, the dosage form is prepared by a process comprising jetmilling a composition comprising 21-23% wt/wt ibuprofen and 73-75% wt/wtacetaminophen. In some cases, the composition subjected to jet millingfurther comprises a surfactant (e.g., sodium lauryl sulfate).

Also described is a method for treating pain (e.g., mild to moderateacute pain) comprising administering a dose of 1, 2 or 3 units of thesolid oral dosage form comprising 325 mg of acetaminophen and 97.5 mg ofibuprofen. In some cases, the administration is 1, 2, 3 or 4 timesdaily.

Also described is a method for treating pain (e.g., mild to moderateacute pain) comprising administering a dose of 1 or 2 units of the solidoral dosage form comprising 500 mg of acetaminophen and 150 mg ofibuprofen. In some cases, the administration is 1, 2, 3 or 4 timesdaily.

Also described is a method for preparing a pharmaceutical composition,comprising jet milling a composition comprising acetaminophen, ibuprofenand a surfactant (e.g. sodium lauryl sulfate), wherein the ratio ofacetaminophen to ibuprofen is 3:1 (w/w), under conditions and for a timeto reduce the particle size of the ibuprofen to a median particle size,on a volume average basis between 2 and 8 μm.

Also describes is a method for preparing a pharmaceutical composition,comprising jet milling a composition comprising acetaminophen, ibuprofenand a surfactant (e.g. sodium lauryl sulfate), wherein the ratio ofacetaminophen to ibuprofen is 3:1 (w/w), under conditions and for a timeto achieve a median bulk particle size between 4 and 15 μm.

In some cases: the [D90] of the ibuprofen in Rapid Maxigesic 325 andRapid Maxigesic 500 is greater than 2 μm (e.g., greater than 3, 4, 5 6,7, 8, 9, 10, 11 or 12 μm) and less than one of: 18 μm, 17 μm 16 μm; 14μm, and 13 μm (preferably 3-17 μm 3-16 μm or 4-15 μm); the [D50] of theibuprofen greater than 1 μm, 1.5 μm, 2 μm, 2.5 μm, 3 μm, 3.5 μm, 4 μm,4.5 μm, 5 μm, 5.5 μm, 6 μm), but less than 12 μm, 10 μm, 9 μm, or 8 μm(preferably 1-11 μm, 1-10 μm, 2-10 μm, 2-9 μm); the [D10] of theibuprofen is less than 7 μm (e.g., 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5,2, or 1.5 μm), but greater than 100 nm; the ratio of [D90] to [D50] isbetween 4:1 and 2:1; and the ratio of [D50] to [D10] is between 3:1 and1.5:1 (all measurements on a volume average basis).

Also described herein is a method for treating pain, e.g., mild tomoderate acute pain, comprising administering to a patient in needthereof a therapeutically effective dose (acetaminophen 975 mg+ibuprofen292.5 mg) of the Rapid Maxigesic 325 unit dosage form (acetaminophen 325mg+ibuprofen 97.5 mg/unit dose) up to 4 times a day (acetaminophen 3900mg+ibuprofen 1170 mg/day).

Also described herein is a method for treating pain, e.g., mild tomoderate acute pain, comprising administering to a patient in needthereof a therapeutically effective dose (acetaminophen 1000mg+ibuprofen 300 mg) of the Rapid Maxigesic 500 unit dosage form(acetaminophen 500 mg+ibuprofen 150 mg/unit dose) up to 4 times a day(acetaminophen 4000 mg+ibuprofen 1200 mg/day).

Additional dosage regimes for Rapid Maxigesic 325 include: 1 unit dosegiven 1, 2, 3 or 4 times daily; 2 unit doses given 1, 2, 3 or 4 timesdaily; and 3 unit doses given 1, 2, 3 or 4 times daily.

Additional dosage regimes for Rapid Maxigesic 500 include: 1 unit dosegiven 1, 2, 3 or 4 times daily and 2 unit doses given 1, 2, 3 or 4 timesdaily.

The dissolution rate of the ibuprofen in a coated tablet containing 97.5mg of ibuprofen is such that when tested in 900 ml of pH 5.8 phosphatebuffer (50 mM) using USP Apparatus II at 50 rpm and 37° C., is such thatat least 75%, 80% or 85% ibuprofen dissolves in 15 min or less (e.g., 14min or less, 13 min or less, e.g., 85% can dissolve in 15 min). Forexample, at least 85% can dissolve in 12-19 minutes.

The dissolution rate the ibuprofen in a coated tablet containing 150 mgof ibuprofen is such that when tested in 900 ml of pH 5.8 phosphatebuffer (50 mM) using USP Apparatus II at 50 rpm and 37° C., is such thatat least 75%, 80% or 85% ibuprofen dissolves in 15 min or less (e.g., 14min or less, 13 min or less, e.g., 85% can dissolve in 15 min). Forexample, at least 85% can dissolve in 12-19 minutes.

The dosage form can include various excipients. For example, the dosageform can include one or more of: a diluent, lubricant, disintegrant,binder and wetting agent. For example, the dosage form can include oneor more of: magnesium stearate, povidone, lactose, microcrystallinecellulose pregelatinized starch, hypromellose, sodium starch glycolate,sodium starch fumarate, sodium lauryl sulfate, and croscarmellosesodium. The tablet can be uncoated or, preferably, coated with asuitable coating agent.

The dry milling apparatus used is preferably a jet mill (e.g., a spiraljet mill).

In another aspect, the disclosure comprises a method for manufacturing apharmaceutical composition as described herein comprising the step ofcombining a composition comprising ibuprofen and acetaminophen preparedby a method described herein or a composition as described herein,together with one of a diluent, lubricant, excipient, disintegrant, andwetting agent, to produce a pharmaceutically acceptable solid dosageform.

The disclosure described herein may include one or more ranges of values(e.g. size, concentration etc.). A range of values will be understood toinclude all values within the range, including the values defining therange, and values adjacent to the range that lead to the same orsubstantially the same outcome as the values immediately adjacent tothat value which defines the boundary to the range.

Throughout this specification, unless the context requires otherwise,the word “comprise” or variations, such as “comprises” or “comprising”will be understood to imply the inclusion of a stated integer, or groupof integers, but not the exclusion of any other integers or group ofintegers. It is also noted that in this disclosure, and particularly inthe claims and/or paragraphs, terms such as “comprises”, “comprised”,“comprising” and the like can have the meaning attributed to it in USPatent law; e.g., they can mean “includes”, “included”, “including”, andthe like.

“Therapeutically effective amount” as used herein with respect tomethods of treatment and in particular drug dosage, shall mean thatdosage that provides the specific pharmacological response for which thedrug is administered in a significant number of subjects in need of suchtreatment. It is emphasized that “therapeutically effective amount,”administered to a particular subject in a particular instance will notalways be effective in treating the diseases described herein, eventhough such dosage is deemed a “therapeutically effective amount” bythose skilled in the art. It is to be further understood that drugdosages are, in particular instances, measured as oral dosages, or withreference to drug concentrations as measured in blood.

Those skilled in the art will appreciate that the disclosure describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the disclosureincludes all such variations and modifications. The disclosure alsoincludes all of the steps, features, compositions and materials referredto or indicated in the specification, individually or collectively andany and all combinations or any two or more of the steps or features.

The present disclosure is not to be limited in scope by the specificembodiments described herein, which are intended for the purpose ofexemplification only. Functionally equivalent products, compositions andmethods are clearly within the scope of the disclosure as describedherein.

Other aspects and advantages of the disclosure will become apparent tothose skilled in the art from a review of the ensuing description.

DETAILED DESCRIPTION

Described herein are various rapid release, solid oral dosage formscontaining 325 mg acetaminophen and 97.5 mg of ibuprofen with highermaximum plasma concentration of ibuprofen compared to a dosage formreferred to as Maxigesic 325. Also described below are various rapidrelease, solid oral dosage forms containing 500 mg acetaminophen and 150mg of ibuprofen with higher plasma concentration of ibuprofen comparedto a dosage form referred to a Maxigesic 500.

Maxigesic 325 tablets contain acetaminophen (325 mg) and ibuprofen (97.5mg) and Maxigesic 500 tablets contain acetaminophen (500 mg) andibuprofen (150 mg). Both are given in single doses of up to threetablets for the lower strength and up to two tablets for the higherstrength. The amount of acetaminophen delivered in a single dose issimilar in both cases being either up to three tablets of Maxigesic 325:acetaminophen 975 mg and ibuprofen 292.5 mg or two tablets Maxigesic500: acetaminophen 1000 mg and ibuprofen 300 mg.

Particle Size

For measurements made using a laser diffraction the term “medianparticle size” is defined as the median particle diameter as determinedon an equivalent spherical particle volume basis. Where the term medianis used, it is understood to describe the particle size that divides thepopulation in half such that 50% of the population on a volume basis isgreater than or less than this size. The median particle size is writtenas: [D₅₀] or D_([50]) or [D50], D50, D(0.50) or D[0.5] or similar. Asused herein [D₅₀] or D_([50]) or [D50], D50, D(0.50) or D[0.5] orsimilar shall be taken to mean median particle size.

The term “Dx of the particle size distribution” refers to the xthpercentile of the distribution on an equivalent spherical particlevolume basis; thus, D90 refers to the 90^(th) percentile, D95 refers tothe 95^(th) percentile, and so forth. Taking D90 as an example this canoften be written as, [D₉₀] or D_([90]) or [D90], D(0.90) or D[0.9] orsimilar. With respect to the median particle size and Dx an upper case Dor lowercase d are interchangeable and have the same meaning.

The term “D(3,2)” is referred to as the area-weighted mean size or theSauter diameter; the term “D(4,3)” is referred to as the volume-weightedmean size. Detailed descriptions of how these values are calculated areknown in the art and can be found in, for example, ISO 9276-2:2014(E).

For many of the materials subject to the methods of this disclosure theparticle size can be easily measured. Where the active material has poorwater solubility and the matrix it is milled in has good watersolubility the powder can simply be dispersed in an aqueous solvent. Inthis scenario the matrix dissolves leaving the active material dispersedin the solvent. This size of the particles in the suspension can then bemeasured by laser light diffraction.

Medicaments

The medicaments of the present disclosure may include thepharmaceutically acceptable material, optionally together with agrinding matrix or at least a portion of the grinding matrix, combinedwith one or more pharmaceutically acceptable carriers, as well as otheragents commonly used in the preparation of pharmaceutically acceptablecompositions.

As used herein “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible.

Pharmaceutical acceptable carriers according to the disclosure mayinclude one or more of the following examples:

-   -   (1) surfactants and polymers including, but not limited to        polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium        lauryl sulfate, polyvinylalcohol, crospovidone,        polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose        derivatives, hydroxypropylmethyl cellulose, hydroxypropyl        cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl        cellulose phthalate, polyacrylates and polymethacrylates, urea,        sugars, polyols, and their polymers, emulsifiers, sugar gum,        starch, organic acids and their salts, vinyl pyrrolidone and        vinyl acetate    -   (2) binding agents such as various celluloses and cross-linked        polyvinylpyrrolidone, microcrystalline cellulose, povidone; and        or    -   (3) filling agents such as lactose monohydrate, lactose        anhydrous, microcrystalline cellulose and various starches; and        or    -   (4) lubricating agents such as colloidal silicon dioxide, talc,        stearic acid, magnesium stearate, calcium stearate, sodium        stearyl fumarate; and or    -   (5) sweeteners such as any natural or artificial sweetener        including sucrose, xylitol, sodium saccharin, cyclamate,        aspartame, and acesulfame K; and or    -   (6) flavoring agents; and or    -   (7) preservatives such as potassium sorbate, methylparaben,        propylparaben, benzoic acid and its salts, other esters of        parahydroxybenzoic acid such as butylparaben, alcohols such as        ethyl or benzyl alcohol, phenolic chemicals such as phenol, or        quarternary compounds such as benzalkonium chloride; and or    -   (8) buffers; and or    -   (9) Diluents such as pharmaceutically acceptable inert fillers,        such as microcrystalline cellulose, lactose, dibasic calcium        phosphate, saccharides, and/or mixtures of any of the foregoing;        and or    -   (10) wetting agents such as docusate sodium, sodium lauryl        sulfate, phospholipids, poloxamer, polysorbate 80, sorbitan        esters, tricaprylin, glyceryl monooleate, myristyl alcohol and        mixtures thereof; and or    -   (11) disintegrants; such as croscarmellose sodium, crospovidone,        sodium starch glycolate, and or    -   (12) effervescent agents such as effervescent couples such as an        organic acid (e.g., citric, tartaric, malic, fumaric, adipic,        succinic, and alginic acids and anhydrides and acid salts), or a        carbonate (e.g. sodium carbonate, potassium carbonate, magnesium        carbonate, sodium glycine carbonate, L-lysine carbonate, and        arginine carbonate) or bicarbonate (e.g. sodium bicarbonate or        potassium bicarbonate); and or    -   (13) other pharmaceutically acceptable excipients.

Example 1: Attritor Milling and Jet Milling Improve Dissolution ofIbuprofen

Attritor milling of an active pharmaceutical ingredient (API), whetherdry or wet, most often takes place in the presence of a milling matrix,i.e., one or more non-active ingredients that can assist in particlesize reduction of the API. For example, in a dry milling process, theAPI can be milled in the presence of lactose or another suitableexcipient. Such milling can be used to reduce the median particle sizeto less than 1,000 nm. Due to the high drug load desired for the presentdosage form, the acetaminophen was used as the milling matrix for theattritor milling studies described below.

Ibuprofen, acetaminophen and sodium lauryl sulfate (SLS) were milled inan attritor mill using the conditions described in Table 1.

TABLE 1 Milling Conditions for Attritor Mill Formula Processingparameters Ingredient % w/w Atritor Mill 0.5 gallon, 1S Ibuprofen 22.5%Media: powder 35:1 ratio Acetaminophen 75.5% Milling speed 500 rpm(APAP) Sodium Lauryl  2.0% Milling time  40 min Sulfate (SLS) Total 100% yield 51.8%

The attritor milling (Table 1) of a mixture of acetaminophen, ibuprofenand sodium lauryl sulfate at a 200 g scale was successful in that themedian particle size of the ibuprofen was reduced to the submicron range(Table 2). Moreover, the dissolution rate of the ibuprofen in the milledmaterial, either attritor milled or jet milled, was faster than that ofthe unmilled API (Table 3). However, the attritor milling yield wasrelatively low due to caking of the milled material.

Co-jet milling was investigated as an alternative approach that mightincrease yield and improve scale. The formula in Table 1 was processedin a 4″ jet mill with 100 prig pressure. As shown in Table 2, theibuprofen within the co-jet milled formulation(acetaminophen/ibuprofen/SLS) was larger in size compared to theibuprofen produced by attritor milling.

TABLE 2 Particle size of ibuprofen Dv10 (μm) Dv50 (μm) Dv90 (μm)Ibuprofen (starting material) 24.2 51.3 94.5 Attritor-milledintermediate 0.282 0.617 2.05 Co-Jet-milled intermediate 1.63 2.73 4.44

Both milled formulations had substantially faster ibuprofen dissolutioncompared to the unmilled formulation, demonstrating that particle sizereduction improved the ibuprofen dissolution rate. However, while theattritor milled material had much smaller particle size for ibuprofenthan the co-jet milled material, the dissolution rates of ibuprofen forboth milled materials (Table 3) were similar. This suggests that theco-jet milled material could overcome the dissolution rate limitedsolubility of ibuprofen, despite the fact that the median particle sizewas greater than 1,000 nm.

TABLE 3 Ibuprofen dissolution rate in acetaminophen/ ibuprofenpowderformulations Prior to miling Attritor milled Co-Jet-milled % % % %% % Time ibuprofen RSD ibuprofen RSD ibuprofen RSD (min) Dissolved n = 3Dissolved n = 3 Dissolved n = 3  2 34.4 4.4  82.5 5.5  96.0 1.3  5 49.26.6  94.9 1.7 103.0 0.4 10 62.3 7.4 100.1 0.5 103.5 0.4 15 68.3 9.6103.5 0.8 104.7 1.2 30 73.1 8.8 103.1 0.2 105.6 0.3 45 75.8 6.7 103.30.9 104.0 0.3 Infinity 91.6 2.1 104.7 1.9 102.9 1.2

Methods

Particle Size

Particle size was measured by first dispersing the sample in 0.1% HPC,0.01N HCl and sonicating for 1 minute with a probe sonicator. Thesonicated samples were added to the laser light diffractor wet sampleunit, filled with 0.1% HPC in 0.01N HCl, stirred for 5 minutes and thenthe sample was measured.

Dissolution Rate

The dissolution of selected powder intermediate formulations was testedusing the USP Apparatus II, with 900 mL of 50 mM pH 5.8 media at 37° C.and a 50 rpm paddle speed. The powder was added to the top of themedia-filled vessels, and samples were assayed by HPLC to obtain theresults.

Example 2: Co-Jet Milling Provides Improved Dissolution for Ibuprofen

The jet milling results suggested that it could provide a means forpreparing a dosage form containing a high drug load of both ibuprofenand acetaminophen. Jet milling was further investigated by manufacturinga powder formulation using two different jet milling methods, both ofwhich employed the formula in Table 4. In the first process, ibuprofenwas jet milled alone and then blended with the acetaminophen, SLS andhydroxypropyl cellulose. In the second process, all four ingredientswere blended and then co-jet milled.

TABLE 4 Formulation for comparisons of jet milling and co-jet millingFormula Ingredient % w/w Ibuprofen  22% Acetaminophen (APAP)  74% SodiumLauryl Sulfate (SLS)  2% Hydroxypropyl cellulose (HPC)  2% Total 100%

The particle size of jet-milled ibuprofen, whether jet-milled alone orco-jet milled with acetaminophen, SLS and HPC was similar, as shown inTable 5.

TABLE 5 Particle size of jet milled and co-jet milled ibuprofen Dv10(μm) Dv50 (μm) Dv90 (μm) Jet milled ibuprofen 1.46 2.53 3.97Co-Jet-milled ibuprofen, 1.31 2.51 4.32 APAP, SLS, HPC

It was unexpectedly found that when ibuprofen was size reduced by co-jetmilling with acetaminophen, SLS and hydroxypropyl cellulose, thedissolution rate was improved relative to ibuprofen that was sizereduced by jet milling in the absence of acetaminophen, SLS andhydroxypropyl cellulose despite the fact that the two methods yieldedsimilarly-sized ibuprofen particles. Table 6 presents data on thedissolution rate of 1) jet-milled ibuprofen that was blended withacetaminophen, SLS and hydroxypropyl cellulose after jet milling; and 2)ibuprofen that was co-jet milled with acetaminophen, SLS andhydroxypropyl cellulose.

It can be seen from the dissolution data in Table 6 that the ibuprofenco-jet milled with acetaminophen, SLS and HPC fully dissolved within 2minutes whereas the ibuprofen milled in the absence of acetaminophen,SLS and HPC took 10 minutes to exceed 85% dissolved. Hence, the presenceof acetaminophen, SLS and HPC in the milling improve the dissolutionrate of similarly sized ibuprofen.

TABLE 6 Dissolution data for jet milled and co-jet milled ibuprofenJet-milled ibuprofen subsequently Ibuprofen co-jet milled with blendedwith acetaminophen, SLS, acetaminophen, SLS, and hydroxypropyl cellulosehydroxypropyl cellulose Time Avg % ibuprofen % RSD Avg % ibuprofen % RSD(min) dissolved (n = 3) dissolved (n = 3)  2 80.0 13.9 100.0 0.6  5 83.114.3 104.5 0.4 10 86.8 11.4 104.6 0.6 15 89.6  9.6 104.8 0.7 30 94.2 6.5 104.8 0.7 45 98.4  3.8 104.6 0.6

The particle size and dissolution rate methods were the same as thosedescribed in Example 1.

Example 3: Preparation of Examples of Rapid Maxigesic 325 Tablets andRapid Maxigesic 500 Tablets

Acetaminophen (75.41% w/w), ibuprofen (22.62% w/w) and sodium laurylsulfate (1.97% w/w) were blended together, and the blend was milledusing a spiral jet mill to achieve a target bulk particle size ofDv50<4.5 micron and Dv90<14 microns. The milled blend (“Drug ProductIntermediate” or DPI) was then blended with excipients and wetgranulated using a high shear mixer and fluid bed dryer. The granulationwas screened/milled, blended with lubricant and compressed into tablets.The tablets were then film coated. Table 7 shows the formulation of themilled intermediate, and Tables 8 and 9 show the tablet formulations.

TABLE 7 Example of Drug Product Intermediate for Rapid Maxigesic 325 and500 Ingredient % w/w Acetaminophen, USP  75.41 Ibuprofen, USP  22.62Sodium Lauryl Sulfate, USP  1.97 100.00

TABLE 8 Example of Tablet Formulation for Rapid Maxigesic (325) RapidMaxigesic 325 Tablet (325 mg acetaminophen, 97.5 mg ibuprofen)Intragranular % w/w mg/tablet Drug Product Intermediate 74.75 431.075.41% APAP 22.62% Ibuprofen 1.97% SLS Microcrystalline Cellulose(Avicel PH101) 9.00 51.9 Lactose Monohydrate (Lactose 310) 11.74 67.7Croscarmellose Sodium (Ac-di-Sol) 2.00 11.5 Povidone (K30) 2.00 11.5Purified Water qs — extragranular Magnesium stearate 0.50 2.9 Totaltablet core 100.00 576.6 Film coating Opadry II 57U18539, White 2.2513.0 (hypromellose, titanium dioxide, polydextrose, talc, maltodextrin,medium chain triglycerides) Total 593.8 mg

TABLE 9 Example of Tablet Formulation for Rapid Maxigesic (500) RapidMaxigesic 500 Tablet (500 mg acetaminophen, 150 mg ibuprofen)Intragranular % w/w mg/tablet Drug Product Intermediate 74.75 663.075.41% APAP 22.62% Ibuprofen 1.97% SLS Microcrystalline Cellulose(Avicel PH101) 9.00 79.8 Lactose Monohydrate (Lactose 310) 11.74 103.8Croscarmellose Sodium (Ac-di-Sol) 2.00 17.7 Povidone (K30) 2.00 17.7Purified Water qs extragranular Magnesium stearate 0.50 4.4 Total tabletcore 100.00 887.0 Film coating Opadry II 57U18539, White 2.00 17.7(hypromellose, titanium dioxide, polydextrose, talc, maltodextrin,medium chain triglycerides) Total 904.7

Particle Size

Several lots of DPI were analyzed to determine the particle size ofibuprofen within the co-jet milled intermediate. All testing wasconducted using laser light diffraction. To measure ibuprofen particlesize the DPI was dispersed in an aqueous media in which theacetaminophen and SLS are soluble (0.1% HPC in 0.01N HCl), leaving onlythe poorly soluble ibuprofen suspended for particle size testing.Specifically, the powder was directly added to the sample chamber andstirred for 5 minutes, then the sample measurement was taken. Theresults of this analysis are in Table 10.

TABLE 10 Particle size data for Rapid Maxigesic DPI Ibuprofen Lot D₁₀(μm) D₅₀ (μm) D₉₀ (μm) 10-1 2.15 4.19 8.22 10-2 1.67 3.03 5.48 10-3 1.723.45 6.95 10-4 2.55 5.26 10.6 10-5 2.35 4.84 9.97 10-6 2.97 6.89 14.310-7 3.15 7.30 14.7

Dissolution Rate

The dissolution of selected tablet formulations was tested using the USPApparatus II, with 900 mL of 50 mM pH 5.8 media at 37° C. and a 50 rpmpaddle speed. One tablet was added to each media-filled vessel, andsamples were assayed by HPLC to obtain the results.

The film coating is present to aid in swallowing, mask taste, and forpharmaceutical elegance. Film coatings typically take a few minutes todissolve, creating a small lag time in the dissolution. To facilitatecomparison, both film coated and uncoated core tablets were studied. Thetablets in these lots were prepared using the DPIs in Table 11. Theresults of this analysis are depicted in Table 11.

TABLE 11 Dissolution of Rapid Maxigesic 325 Ibuprofen dissolution in pH5.8 buffer LOT 12-A LOT 12-B LOT 12-C LOT 12-D LOT 12-E (coated)(coated) (uncoated) (uncoated) (uncoated) avg % RSD avg % RSD avg % RSDavg % RSD avg % RSD time % n = 6 % n = 6 % n = 6 % n = 6 % n = 6  5  5418.1  28 28.2  47 10.2 50 9.4  63 7.6 10  94 5.4 78 7.8 80  4.6 87 2.2 95 2.3 15  98 2.4 93 2.5 94  0.3 96 0.9 101 0.9 20 100 1.6 96 1.4 951    98 1.6 102 0.7 30 100 1.6 97 0.8 96  0.3 97 1.6 102 0.8 45 101 0.898 0.5 96  0.6 97 1.9 102 0.6

In a separate study, the dissolution rate of ibuprofen in two differentlots of Rapid Maxigesic 325 tablets (prepared as described above) wascompared to that of Maxigesic Tablets 325 (measured in pH 5.8 phosphatebuffer, as described above). The results are presented in Table 12. Asimilar comparison was performed for Rapid Maxigesic 500 and Maxigesic500 tablets. The results are shown in Table 13.

TABLE 12 Dissolution of Rapid Maxigesic 325 and Maxigesic 325 Tablets inpH 5.8 Phosphate Buffer Rapid Maxigesic Rapid Maxigesic 325 (Lot X) 325(Lot Y) Maxigesic 325 % % % % % % Time Ibuprofen RSD Ibuprofen RSDIbuprofen RSD (min) dissolved (n = 12) dissolved (n = 12) dissolved (n =12)  5 57 13.7  81 8.1 42 12.2  10 91 3.0 95 1.6 59 5.6 15 95 2.9 98 1.769 5.5 20 97 1.3 99 1.3 77 4.3 30 98 1.2 100  1.0 84 4.5 45 99 1.0 100 1.0 89 3.1 F2 34 28 Reference

TABLE 13 Dissolution of Maxigesic 500 and Rapid Maxigesic 500 Tablets inpH 5.8 Phosphate Buffer Rapid Maxigesic 500 (Lot Z) Maxigesic 500 Time %Ibuprofen % Ibuprofen (min) dissolved % RSD (n = 6) dissolved % RSD (n =6) 5 80.8 8.9 42.6 14.5 10 95.6 3.1 65.2 11.3 15 98.1 2.2 72.2 6.9 2099.7 1.5 77.1 3.3 30 100.8 1.3 83.1 2.7 45 100.8 1.5 88.1 2.2 F2 34Reference

From the results describe above, it can be seen that it is possible toprepare solid oral dosages forms with greatly improved dissolution ofibuprofen, despite the ibuprofen having a median particle size (on avolume average basis) that is larger than 1 micron.

Example 4: Pharmacokinetic Analysis of Rapid Maxigesic 325 in Comparisonto Maxigesic 325

A clinical study was undertaken in which the Cmax for ibuprofen and theCmax for acetaminophen was assessed in both the fasting and fed states.

This data was tested using individual 90% CI, two-tailed, unpairedt-tests. Comparisons were made between Maxigesic Rapid 325 and Maxigesic325 in either fed or fasting conditions. This allows for a significantdifference to be detected at 10% or P≤0.1. The study protocol alreadyused a 90% CI to calculate the mean differences in the mean logtransformed data of acetaminophen and ibuprofen.

For acetaminophen in the fasting state there was no statisticallysignificant difference in Cmax between the formulations Table 13.

TABLE 13 Acetaminophen fasting Cmax Maxigesic 325 and Rapid Maxigesic325 Difference between means −459.1 ± 1665 90% confidence interval −3243to 2325 Percentage difference between means −2.99%

For ibuprofen in the fasting state there was a statistically significantdifference in Cmax between the formulations (Table 14)

TABLE 14 Ibuprofen fasting Cmax Maxigesic 325 and Rapid Maxigesic 325Difference between means −2727 ± 1443 90% confidence interval −5138 to−315.6 Percentage difference between means 11.93%

This is an important advantage of the present dosage forms since dosingon an empty stomach is advised in order to achieve fast onset of painrelief.

For acetaminophen in the fed state there was no statisticallysignificant difference in Cmax between the formulations (Table 15).

TABLE 15 Acetaminophen fed Cmax Maxigesic 325 and Rapid Maxigesic 325Difference between means −813.1 ± 996 90% confidence interval −2478 to851.7 Percentage difference between means 7.82%

For ibuprofen in the fed state there was no statistically significantdifference in Cmax between the formulations, although a significantincrease was again observed (Table 16)

TABLE 16 Ibuprofen fed Cmax Maxigesic 325 and Rapid Maxigesic 325Difference between means 2344 ± 1362 90% confidence interval 67.02 to4622 Percentage difference between means 12.68%

To summarize, in both studies, fed and fasting, the Cmax of ibuprofen inMaxigesic Rapid (325) was significantly higher than Maxigesic (325). The90% confidence intervals did not overlap with 0 which shows asignificant difference between the means. There was a difference of >11%between the ibuprofen means, consistent with the Maxigesic Rapidformulation delivering higher Cmax drug concentrations of ibuprofen.

Example 5: Pharmacokinetic Analysis of Maxigesic 325

A pharmacokinetic analysis of the Maxigesic 325 formulation describedabove was conducted under fed and fasting conditions. The results ofthis study are presented in Tables 17-20.

TABLE 17 Ibuprofen PK Values for Maxigesic Rapid 325 in Fastingcondition Pharmacokinetic Parameter (N = 30) C_(max) (ng/ml) 25579.823 ±5996.24 AUC_(0→t) (ng · h/ml)  91888.7 ± 24015.73 AUC_(0→∞) (ng · h/ml) 95621.9 ± 28252.68 t_(max) (h) * 1.25 (0.25-3.00) K_(el) (I/h)   0.3076± 0.06 t_(1/2e1) (h)    2.35 ± 0.57 AUC_(0→t)/AUC_(0→∞) %   96.82 ± 3.22

TABLE 18 Ibuprofen PK Values for Maxigesic Rapid 325 in Fed ConditionPharmacokinetic Parameter (N = 30) C_(max) (ng/ml) 20834.673 ± 5506.39AUC_(0→t) (ng · h/ml)  71286.1 ± 16546.13 AUC_(0→∞) (ng · h/ml)  73449.6± 17660.44 t_(max) (h) * 1.25 (0.75-6.00) K_(el) (I/h)   0.3222 ± 0.05t_(1/2e1) (h)    2.19 ± 0.31 AUC_(0→t)/AUC_(0→∞) %   97.25 ± 1.42

TABLE 19 Acetaminophen PK Values for Maxigesic Rapid 325 in FastingCondition Pharmacokinetic Parameter ® (N = 29) C_(max) (ng/ml) 14877.280± 5969.64 AUC_(0→t) (ng · h/ml)  44637.6 ± 11784.46 AUC_(0→∞) (ng ·h/ml)  47437.2 ± 13053.06 t_(max) (h) * 0.75 (0.25-2.00) K_(el) (I/h)  0.2233 ± 0.05 t_(1/2e1) (h)    3.25 ± 0.75 AUC_(0→t)/AUC_(0→∞) %  94.43 ± 2.54

TABLE 20 Acetaminophen PK Values for Maxigesic Rapid 325 in FedCondition Pharmacokinetic Parameter (N = 30) C_(max) (ng/ml) 11214.182 ±4084.46 AUC_(0→t) (ng · h/ml)  39826.6 ± 11211.91 AUC_(0→∞) (ng · h/ml) 42381.0 ± 12086.45 t_(max) (h) * 1.25 (0.50-6.00) K_(el) (I/h)   0.2303± 0.03 t_(1/2e1) (h)    3.05 ± 0.37 AUC_(0→t)/AUC_(0→∞) %    94.16 ±2.30

OTHER EMBODIMENTS

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the disclosure has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the disclosure following, in general, theprinciples of the disclosure and including such departures from thedisclosure that come within known or customary practice within the artto which the disclosure pertains and may be applied to the essentialfeatures hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims.

The invention claimed is:
 1. A solid oral dosage form comprising 325 mgof acetaminophen and 97.5 mg of ibuprofen or 500mg of acetaminophen and150 mg of ibuprofen, and a surfactant, wherein the ibuprofen is in theform of particles having a Dv50 between 1 and 9 μm and at least 85% to95% the ibuprofen in the solid oral dosage form dissolves in 15 minutesor less when tested using USP Apparatus II (paddles) set to rotationspeed of 50 rpm in 900 mL of 50 mM pH 5.8 phosphate buffer at 37° C. 2.The solid dosage form of claim 1, wherein the ibuprofen has a Dv10between 1 and 3 μm.
 3. The solid dosage form of claim 1, wherein theibuprofen has a Dv90 between 3 and 16 μm.
 4. The solid dosage form ofclaim 1, wherein the ibuprofen has a Dv50 between 2 and 8 μm, a Dv10between 1 and 3 μm and a Dv90 between 4 and 16 μm.
 5. The solid oraldosage form of claim 1, wherein the dosage form is a tablet.
 6. Thesolid oral dosage form of claim 5, wherein the tablet is coated.
 7. Thesolid oral dosage form of claim 1, wherein the Dv90 to Dv50 ratio isbetween 4:1 and 1.5:1.
 8. The solid oral dosage form of claim 1, whereinthe Dv90 to Dv50 ratio is between 3:1 and 1.5:1.
 9. The solid oraldosage form of claim 1, wherein the Dv50 to Dv10 ratio is between 4:1and 1.5:1.
 10. The solid oral dosage form of claim 1, wherein the Dv50to Dv10 ratio is between 3:1 and 1.5:1.
 11. The solid oral dosage formof claim 3, wherein the solid oral dosage form is a coated tablet. 12.The solid oral dosage form of claim 1, prepared by a process comprisingjet milling a composition comprising 21-23% wt/wt ibuprofen and 73-75%wt/wt acetaminophen and a surfactant.
 13. The solid oral dosage form ofclaim 1, wherein the surfactant is sodium lauryl sulfate.
 14. A methodfor treating pain comprising administering a dose of 1, 2 or 3 units ofthe solid oral dosage form of claim 1 comprising 325 mg of acetaminophenand 97.5 mg of ibuprofen.
 15. The method of claim 14, wherein theadministration is 1, 2, 3 or 4 times daily.
 16. A method for treatingpain comprising administering a dose of 1 or 2 units of the solid oraldosage form of claim 1 comprising 500 mg of acetaminophen and 150 mg ofibuprofen.
 17. The method of claim 16, wherein the administration is 1,2, 3 or 4 times daily.
 18. The method of claims 14, wherein the pain ismild to moderate acute pain.
 19. The solid oral dosage form of claim 12,wherein the surfactant is sodium lauryl sulfate.
 20. The solid oraldosage form of claim 4, wherein the Dv90 to Dv50 ratio is between 3:1and 1.5:1.
 21. The solid oral dosage form of claim 4, wherein the Dv50to Dv10 ratio is between 3:1 and 1.5:1.
 22. The solid oral dosage formof claim 20, wherein the Dv50 to Dv10 ratio is between 3:1 and 1.5:1.23. The solid oral dosage form of claim 1, where the ibuprofen in thesolid oral dosage form completely dissolves in 15 minutes or less whentested using USP Apparatus II (paddles) set to rotation speed of 50 rpmin 900 mL of 50 mM pH 5.8 phosphate buffer at 37° C.
 24. The solid oraldosage form of claim 1, where the ibuprofen in the solid oral dosageform completely dissolves in 10 minutes or less when tested using USPApparatus II (paddles) set to rotation speed of 50 rpm in 900 mL of 50mM pH 5.8 phosphate buffer at 37° C.
 25. The solid oral dosage form ofclaim 1, where the ibuprofen in the solid oral dosage form completelydissolves in 5 minutes or less when tested using USP Apparatus II(paddles) set to rotation speed of 50 rpm in 900 mL of 50 mM pH 5.8phosphate buffer at 37° C.
 26. The solid oral dosage form of claim 4,where the ibuprofen in the solid oral dosage form completely dissolvesin 15 minutes or less when tested using USP Apparatus II (paddles) setto rotation speed of 50 rpm in 900 mL of 50 mM pH 5.8 phosphate bufferat 37° C.
 27. The solid oral dosage form of claim 4, where the ibuprofenin the solid oral dosage form completely dissolves in 10 minutes or lesswhen tested using USP Apparatus II (paddles) set to rotation speed of 50rpm in 900 mL of 50 mM pH 5.8 phosphate buffer at 37° C.
 28. The solidoral dosage form of claim 4, where the ibuprofen in the solid oraldosage form completely dissolves in 5 minutes or less when tested usingUSP Apparatus II (paddles) set to rotation speed of 50 rpm in 900 mL of50 mM pH 5.8 phosphate buffer at 37° C.